Functional Vitamin B12 Deficiency with Normal Lab Results: When Symptoms Don’t Match the Numbers

You can have classic symptoms of vitamin B12 deficiency—numbness, burning feet, clumsiness, memory fog, mood changes—while your serum vitamin B12 result sits in the “normal” range. That mismatch is called functional vitamin B12 deficiency: inside your cells, vitamin B12–dependent reactions are failing even though the standard blood test looks okay. ^[1]

Vitamin B12 is essential for two major enzyme systems: methionine synthase, which uses vitamin B12 to convert homocysteine to methionine (crucial for methylation and myelin), and methylmalonyl-CoA mutase, which uses vitamin B12 to convert methylmalonyl-CoA to succinyl-CoA (crucial for fatty-acid and energy metabolism). When vitamin B12 is insufficient where it counts—inside cells—homocysteine and methylmalonic acid tend to rise. Meanwhile, your total serum vitamin B12 may remain in range because it measures vitamin B12 attached to several carrier proteins, including forms that are not delivering vitamin B12 into cells. ^[2]

The routine blood test reports total vitamin B12 (on all carriers). Most circulating vitamin B12 binds haptocorrin, a transport protein that does not deliver vitamin B12 into tissues; only vitamin B12 bound to transcobalamin (called holotranscobalamin, or “active B12”) is readily taken up by cells. If haptocorrin is high—as in some liver diseases, inflammation, or certain malignancies—the total vitamin B12 result can look normal or high while cells are still starved. Assay interferences (including intrinsic factor antibodies in pernicious anemia) can also produce falsely normal or elevated values. ^[3]

Several studies and reviews warn that elevated or normal serum vitamin B12 does not guarantee sufficiency and, in some contexts, may flag underlying illness rather than replete vitamin B12 status. ^[4]

Recreational or occupational nitrous oxide oxidizes the cobalt in vitamin B12 and acutely inactivates it, producing a functional deficiency that can cause myeloneuropathy—even if serum vitamin B12 is not low at first. ^[5]

Long-term metformin and chronic use of proton pump inhibitors or H2 blockers reduce vitamin B12 absorption. Guidelines and safety advisories recommend checking vitamin B12 in symptomatic or high-risk metformin users. Acid suppression can compound the effect. ^[6]

High haptocorrin from liver disease or inflammation can raise total serum vitamin B12 while active delivery is low. Intrinsic factor antibodies in pernicious anemia can bind the assay reagents and falsely normalize or elevate the reported value. ^[3]

Neurologic symptoms (paresthesias, gait ataxia, cognitive changes) may precede anemia or macrocytosis, so blood counts can be normal while nerves are affected. ^[7]

• Neurologic: burning or numb feet, loss of vibration sense, pins and needles, poor balance, gait changes, memory trouble, mood changes, or “brain fog.” ^[8]
• Hematologic: anemia and macrocytosis are not required; many people with neurologic vitamin B12 deficiency present without anemia. ^[7]
• Other: Glossitis or painful, red tongue; fatigue; reduced exercise tolerance. ^[9]

If these symptoms persist—especially in people with risk factors (older age, vegetarian or vegan diet without fortification, gastrointestinal surgery, inflammatory bowel disease, autoimmune gastritis, long-term metformin or acid suppression)—think beyond the single total vitamin B12 number. ^[10]

If results are low-normal or do not match the clinical picture, order methylmalonic acid (a sensitive functional marker) and, if available, holotranscobalamin. Many primary-care guidelines advise confirming with methylmalonyl acid in patients who have symptoms or are at risk with low-normal totals. ^[11]

• Methylmalonic acid rises in vitamin B12 deficiency and in kidney disease; interpret in context of estimated glomerular filtration rate. ^[12]
• Homocysteine rises in vitamin B12 deficiency but also with folate or vitamin B6 deficiency and in hypothyroidism; it is useful but less specific. ^[13]

Holotranscobalamin reflects vitamin B12 available for cellular uptake and can identify deficiency earlier than total vitamin B12 in many settings. Evidence suggests holotranscobalamin and methylmalonic acid, especially together, improve diagnostic accuracy. Some studies use a combined index (“4cB12”) incorporating total vitamin B12, holotranscobalamin, methylmalonic acid, and homocysteine to define true tissue deficiency. ^[14]

Ask about diet (long-term vegan without fortification), gastrointestinal history (gastric bypass, ileal disease), autoimmunity (pernicious anemia), and medications (metformin, proton pump inhibitors, H2 blockers, nitrous oxide exposure). Testing for intrinsic factor and parietal cell antibodies is appropriate when pernicious anemia is suspected. ^[9]

“True” deficiency means low body stores (for example, from malabsorption or dietary insufficiency). Functional deficiency means vitamin B12 is present in the blood but not working where needed—because it is inactivated (nitrous oxide), trapped on the wrong carrier, not getting into cells, or intracellular biochemistry is impaired. In lived experience, both scenarios look the same to the nervous system and bone marrow; both deserve evaluation and treatment. ^[5]

Neurologic injury from vitamin B12 deficiency can be partially irreversible if treatment is delayed. Earlier intervention—especially when symptoms are mild—improves the odds of full recovery. ^[1]

If clinical suspicion is high (neurologic symptoms or significant risk factors) and functional markers support deficiency, start treatment while completing the work-up.

High-dose oral vitamin B12 (cyanocobalamin 1–2 mg daily) is as effective as intramuscular vitamin B12 for most patients and is convenient and inexpensive. ^[15]

Intramuscular vitamin B12 is reasonable for severe neurologic symptoms, profound deficiency, or malabsorption states where rapid repletion is critical. Many patients then transition to maintenance oral therapy. ^[15]

• Review and adjust metformin and acid-suppressing regimens if feasible; at minimum, monitor and supplement in at-risk patients. ^[16]
• Identify pernicious anemia and long-term needs for lifelong supplementation. ^[9]
• Counsel on dietary sources or fortification for those on vegan or highly restricted diets. ^[10]
• In suspected nitrous oxide exposure, stop exposure immediately and treat aggressively; neurologic recovery may be incomplete if treatment is delayed. ^[5]

Neurologic symptoms often begin to improve over weeks to months, with earlier and milder cases recovering more fully. Hematologic changes (if present) normalize earlier. Persistently abnormal methylmalonic acid or homocysteine after treatment suggests ongoing deficiency, non-adherence, or another cause such as chronic kidney disease. ^[11]

• Symptoms or signs suggest deficiency (neuropathy, cognitive changes, anemia or macrocytosis, glossitis) even if total vitamin B12 looks normal:
• Order methylmalonic acid and consider holotranscobalamin; check homocysteine if available. Screen for renal impairment and thyroid disease to interpret results correctly. ^[18]
• If functional markers are elevated (or suspicion is high with risk factors), begin vitamin B12 therapy and investigate the cause (diet, medications, pernicious anemia, nitrous oxide). ^[15]
• Reassess symptoms and markers after repletion; continue maintenance in ongoing malabsorption and educate patients on long-term monitoring. ^[9]

Yes. Neurologic symptoms can appear in the absence of anemia or macrocytosis; that is one reason functional deficiency is often missed in early stages. ^[7]

Possibly. High totals occur in liver disease, inflammation, and some cancers, and can also result from assay interference. In these cases, holotranscobalamin, methylmalonic acid, and homocysteine provide better insight into tissue-level status. ^[3]

Holotranscobalamin reflects the active fraction that cells can use and often detects deficiency earlier than total vitamin B12. Many experts pair holotranscobalamin with methylmalonic acid (or use the combined index 4cB12) for the best diagnostic accuracy. Availability varies by region. ^[14]

Kidney disease elevates methylmalonic acid, so results must be interpreted alongside kidney function. Homocysteine rises with folate or vitamin B6 deficiency and with hypothyroidism; that is why homocysteine is supportive but not specific. ^[18]

Long-term metformin, proton pump inhibitors, and H2 blockers are frequent contributors; nitrous oxide exposure can cause acute functional deficiency. If you use these and have compatible symptoms, ask about second-line testing. ^[6]

For most people, high-dose oral vitamin B12 (1–2 mg daily) corrects deficiency as effectively as injections; intramuscular dosing is preferred when neurologic symptoms are severe or malabsorption is profound and rapid repletion is needed. ^[15]

• Normal total vitamin B12 does not rule out functional deficiency. If symptoms suggest deficiency, escalate to methylmalonic acid and holotranscobalamin, and consider homocysteine with its caveats. ^[11]
• Recognize high-risk settings: metformin, acid suppression, nitrous oxide, vegan diet without fortification, pernicious anemia, and gastrointestinal surgery. ^[17]
• Treat early to protect nerves; use high-dose oral vitamin B12 for most, reserve intramuscular therapy for severe cases, and fix underlying causes. ^[15]

Educational content only; not a substitute for personal medical advice.